tbuckley/cabot-search huggingface dataset:
A first-in-human, open-label, phase I trial of daily oral PCLX-001, an NMT inhibitor, in patients with relapsed/refractory B-cell lymphomas and advanced solid tumors.
Authors: Randeep S. Sangha, Rahima Jamal, Jennifer L. Spratlin, John Kuruvilla, Laurie Helen Sehn, Michael Weickert, Luc G. Berthiaume, John Robert Mackey
Journal: Journal of Clinical Oncology (2023)

e15094 Background: Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways driving cancer cell biology. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. PCLX-001 is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC 50 of 5nM and 8nM, respectively). In vitro, hematologic cancer cell lines were exquisitely sensitive to PCLX-001. PCLX-001 regressed subcutaneous tumors in xenograft models derived from lymphoma cell lines, as well as in a refractory DLBCL patient derived xenograft model. PCLX-001 also demonstrated anticancer activity in multiple solid tumor xenograft models. Based on pre-clinical data, we hypothesized that PCLX-001 would be safe, tolerable, and active as a novel oral cancer therapeutic. Methods: Patients with relapsed/refractory B-cell lymphomas and advanced solid tumors are being enrolled in a multicenter, open label, standard phase I dose escalation design to determine feasibility, maximum tolerated dose (MTD), and pharmacokinetics of PCLX-001 monotherapy. Seven dose levels are being studied: 20 mg, 40 mg, 70 mg, 100 mg, 140 mg, 200 mg, and 280 mg. Dose limiting toxicity (DLT) is defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, Gr 4 ANC ≥ 7 days, febrile neutropenia, or clinically significant &gt; Gr 3 non-hematologic toxicity. Results: Eighteen evaluable patients (3 relapsed B-cell lymphoma; 15 advanced solid tumor) have been accrued through dose level six (200 mg cohort) without DLT. No attributable Gr 3 or 4 toxicities have been identified. Noncompartmental pharmacokinetic (PK) analyses demonstrate rapid oral absorption, a terminal half-life of approximately 10 hours, rapid achievement of steady state, and no induction of metabolism. PCLX-001 trough plasma concentrations at higher dose cohorts exceed the EC 90 required to inhibit cultured cancer cells. Conclusions: PCLX-001 is safe and well tolerated up to the 200 mg daily dose. Our results support the ongoing development of PCLX-001 as an oral daily therapy for the treatment of patients with cancer. Updated study results will be presented, summarizing the safety, MTD, and PK outcomes in PCLX-001 treated patients. Preliminary clinical activity will be determined in 20 patient dose expansion cohorts of relapsed/refractory B-cell lymphomas, and selected advanced solid tumors following the identification of PCLX-001 MTD. Clinical trial information: NCT04836195 .
Adverse events in real-world patients covered by Medicare with metastatic pancreatic ductal adenocarcinoma who received first-line FOLFIRINOX.
Authors: Gabriela Dieguez, Samantha Tomicki, Paul Cockrum, Jared Hirsch, Prachi Bhatt, George P. Kim
Journal: Journal of Clinical Oncology (2023)

e16280 Background: FOLFIRINOX (FFX) is often associated with side effects and toxicity. This study examines real-world incidence of adverse events (AEs) and associated costs among Medicare fee-for-service (FFS) beneficiaries with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving first-line (1L) FFX. Methods: We identified patients aged 65+ with a record indicating a diagnosis of mPDAC between 2018-2021 in the Medicare Parts A, B, and D 100% Research Identifiable Files (RIF) data. Patients were required to have at least two malignant neoplasm of pancreatic duct diagnosis codes on different dates AND at least one diagnosis of a metastasis anytime on or after the first pancreatic cancer diagnosis. Patients with end-stage renal disease were excluded. Patients were assigned to cohorts based on drugs present within a 48-hour (2-day) period of a FFX chemo infusion cycle: 1) FFX with all 4 component drugs (oxaliplatin, irinotecan, leucovorin, 5-FU bolus and infusion), 2) FFX with no 5-FU bolus, but with 5-FU infusion, 3) FFX with a 5-FU bolus, but no 5-FU infusion, 4) FFX with no 5-FU of any kind and, 5) FFX with no leucovorin. Lines of therapy (LOTs) were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. Incidence rates of adverse events per administration for each cohort were determined along with the total costs of care and growth factor spending per administration. Results: We identified a total of 45,755 administrations of 1L FFX. Administrations of FFX without 5-FU of any kind (N = 842 administrations) had the lowest incidence of AEs (nausea 21.4%, neutropenia 12.5%, anemia 11.4%, fatigue 9.7%, diarrhea 10.1%, and neuropathy 5.9%), total cost of care ($6,715), and growth factor spending ($792). Administrations with all four FFX component drugs (N = 15,565 administrations) had the highest incidence of neutropenia (27.5%) and fatigue (17.5%) as well as the highest total cost of care ($7,515) and growth factor spending ($1,761). Conclusions: Among patients receiving 1L FFX, administrations with all four component drugs were associated with the highest incidence of adverse events as well as the highest total cost of care per administration cycle. In particular, neutropenia was seen in over twice as many administration cycles in patients receiving FFX with all four components (27.5%) compared to those receiving FFX with no 5-FU of any kind (12.5%). A higher incidence of neutropenia contributes to higher growth factor utilization and therefore higher costs.
Apixaban versus rivaroxaban for treatment of acute deep venous thrombosis in patients with cancer.
Authors: Brittany Miles, Peter Young, Megan Bradley, James David Mackey
Journal: Journal of Clinical Oncology (2023)

12113 Background: Direct oral anticoagulants (DOAC) such as Apixaban and Rivaroxaban are increasingly used for the treatment of acute venous thromboembolism (VTE) over traditional vitamin K antagonists. Malignant neoplasms predispose to acute VTE and clinical management necessitates anticoagulation to prevent further complications. We compare Apixaban to Rivaroxaban for the treatment of acute VTE in the setting of malignancy with the endpoint of chronic deep venous thrombosis (DVT) development after 2 years. Methods: The TriNetX Research network was used for this study. TriNetX provides access to anonymized medical record information on more than 107 million patients in 76 large healthcare organizations. Two cohorts were created for this study using the International Classification of Disease-10 (ICD-10) codes. All patients were required to have a diagnosis of breast (C50), lung (C34), colon (C18), or prostate cancer (C61). All were diagnosed with acute deep venous thrombosis (DVT) of the lower extremities (I82.409). One cohort was treated with rivaroxaban while the other was treated with apixaban within 3 days of DVT diagnosis. Each cohort was excluded from being treated with the other anticoagulant. The cohorts were balanced for age, race, gender, and ethnicity, then evaluated for the development of chronic DVT (I82.509) within the subsequent twelve months. Results: The development of chronic DVT was significantly more common in the apixaban cohort, with a risk ratio of 1.36 (95% CI (1.12,1.65), p-value 0.0015). See table. Conclusions: Patients with acute VTE in the setting of malignancy were at a significantly higher risk of developing chronic DVT following treatment with Apixaban compared to those who received Rivaroxaban at 2 years post-treatment. These results may contribute to increased discussion between physicians and patients when deciding between these two direct oral anticoagulants for the management of acute VTE. Diagnosis of chronic DVT in cancer patients treated with apixaban and rivaroxaban. [Table: see text]
Cure-PROs: Next-generation targeted protein degraders.
Authors: Sarah F. Giardina, Elena Valdambrini, Michael Peel, Manny D. Bacolod, Mace L. Rothenberg, Richard B. Lanman, J. David Warren, Francis Barany
Journal: Journal of Clinical Oncology (2023)

e15101 Background: Many proteins, including transcription factors and scaffolding proteins, are not amenable to targeting by traditional small molecule inhibitors due to the lack of a well-defined binding pocket or active site. Proteolysis-Targeting Chimeras (PROTACs) are a new class of hetero-bifunctional molecules that bind both a target protein and an E3 ubiquitin ligase, bringing the two into proximity for appending ubiquitin, and subsequently marking the target protein for proteasomal degradation. Currently, thirteen PROTACs are in clinical trials for oncology indications. However, the clinical utility of PROTACs is challenged by their large size and long development timelines. Also, resistance mutations in the E3 ligase or transporter overexpression inevitably evolve. Thus, a new platform for small-molecule degraders that enables ultra-rapid drug development timelines, efficient cellular uptake, and can be developed to overcome innate and acquired drug resistance is needed. Methods: Coferons, developed in our laboratory, are small molecules that self-assemble upon binding to a target, where they form reversible covalent dimers through bio-orthogonal linker chemistries. We have combined features of the Coferon platform and PROTACs to generate CURE-PROs (Combinatorial Ubiquitination REal-time PROteolysis), consisting of one target protein ligand and one E3 ligase ligand that form reversible heterodimers that lead to targeted protein degradation within cells. By modifying known ligands for BRD4, and the E3 ubiquitin ligases Cereblon, VHL, and MDM2, with linkers able to reversibly join the BRD4 to the ligase ligands, we synthesized libraries of CURE-PRO monomers that can be combined to create thousands of CURE-PRO dimer combinations. We explored whether this platform could yield meaningful BRD4 degradation in vitro and in vivo. Results: Rapid combinatorial cell-based screening identified several BRD4-E3 ligase CURE-PRO combinations that induced greater than 50% BRD4 degradation, with the most promising CURE-PRO pairs achieving more than 95% protein degradation. Consistent with a PROTAC mechanism-of-action, successful CURE-PRO combinations confirmed significant protein degradation which was inhibited by proteasome inhibitors or competition with parent ligands. Significant BRD4 degradation was also observed in mice bearing bilateral human xenograft tumors, confirming CURE-PRO proof-of-mechanism in vivo. Conclusions: The combinatorial nature of our platform has the potential to significantly reduce synthesis time and effort to identify the optimal linker length and E3 ligase for each target protein. The CURE-PRO platform consists of expanding libraries of monomers for both additional oncoprotein targets as well as E3 ligases, which can be redeployed to shorten lead development timelines.
Penpulimab combined with anlotinib therapy in patients with advanced refractory solid tumors: A single-center, observational, prospective study.
Authors: Shansi Zhou, Tao Wang
Journal: Journal of Clinical Oncology (2023)

e15129 Background: Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced refractory solid tumors. In advanced NSCLC patients,this conclusion has been confirmed in a number of clinical studies such as WJOG@Be Study and JVDF. A clinical study, KEYNOTE-524/Study116, demonstrated survival benefits from this combination model in liver cancer, and a similar trend was seen in patients in the bile duct cancer study presented.Penpulimab + anlotinib is an important combination immunotherapy. Here we described the results of safety, and clinical efficacy of penpulimab combined with anlotinib in patients with advanced solid tumors, the serum cytokine levels, and peripheral blood T lymphocyte populations were detected simultaneously. Methods: 17 cases with advanced cancers including lung, gallbladder, cholangiocarcinoma, and hepatocellular Carcinoma were treated since January 2022. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or intolerabletoxicity. Imaging was performed every 6 weeks for thefirst year of therapy. Blood samples were collected from patients prospectively. Serum interleukin (IL-2, IL-4, IL-6, IL-10), tumornecrosis factor-α(TNF-α), interferon-γ(IFN-γ) and circulating immune cell subsets were measured at baseline and after two cycles of treatment via flow cytometry. Results: From January 2022 to December 2022, 17 patients had received the combination therapy of penpulimab plus anlotinib (median age 68.8yrs [range 51-83],52.9% males, 100% ECOG PS 1. Most patients had received frist line treatments for metastatic disease (82.4%). Of 13 pts who have had at least one tumor assessment, the ORR（objective remission rate ）was 35.29% (6 PRs) and DCR was 58.82% (4 SDs). The median PFS was 7.98 months (95% CI: 1.68-NE months).Up to now, eight responders remain in response.The most common adverse reactions included：hypertension was 1/17（5.9%）, Hand foot syndrome was 1/17（5.9%）, loss of appetite was 1/17（5.9%）.There were no grade 3 and above treatment-related adverse events. Conclusions: The combination of penpulimab plus anlotinib as a treatment for advanced refractory solid tumor showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable treatment strategy for advanced refractory solid tumor patients.
Analysis and optimization of equitable US cancer clinical trial center access by travel time.
Authors: Hassal Lee, Alexander Bates, Andrea Marshall, Shawneequa Callier, Nyasha Chambwe, Tobias Janowitz
Journal: Journal of Clinical Oncology (2023)

6524 Background: Racially minoritized and socioeconomically disadvantaged populations are underrepresented in cancer clinical trials. Data-driven, quantitative approaches are required to address this inequity. Here, we systematically analyze the geographical distribution of self-identified racial and socioeconomic demographics within commuting distance to cancer clinical trial centers and all hospitals U.S.-wide. Methods: We calculate self-identified racial and socioeconomic demographics of populations living within 30-, 60-, and 120-minute one-way driving commute times from U.S. cancer clinical trial centers and all U.S. hospitals. Data sources include the U.S. 2020 census (for race and socioeconomic data), OpenStreetMaps (for calculation of commuting times), NCT trial registry (for cancer clinical trial quantification), NCI Designated Cancer Centers List, Nature Index of Cancer Research Health Institutions and National Homeland Infrastructure Foundation-Level Data (for U.S.-wide hospital and cancer clinical trial center identification). Data analysis was conducted in R, and Ggplot2 used for all data visualizations. Results: Analysis of clinical trial numbers between 2012–2022 identified 78 high-volume U.S. cancer trial centers. Compared to U.S. national averages, these centers are in areas with socioeconomically more affluent populations (+27.6K USD (95% CI +23.1 to 32.8K) median income unpaired mean difference; -0.073 (95% CI -0.063 to -0.084) deprivation index unpaired mean difference), with higher proportions of affluent self-identified White individuals (+10.1% unpaired mean difference (95% CI +6.8 to +13.7%)). The top 10 th percentile of all U.S. hospitals (N=7,623) show a range of absolute sum difference from 2.4% to 35% from equal racial representation of White, Black/African American and Asian/Mixed/Other groups. For each U.S. city above 500,000 inhabitants, we compile map overlays that display all prospective hospitals within commutable distance to racially diverse and socioeconomically disadvantaged populations. These maps may inform the design of future clinical trials or investigations in enrollment and retention strategies for clinical trials. Conclusions: Our analysis identifies biases in the sociodemographics of populations living within commuting distance to U.S.-based cancer trial sites and enables the determination of more equitably commutable prospective satellite hospital sites that could be mobilized for enhanced racial and socioeconomic representation in clinical trials. Other recruitment barriers still need to be tackled to ensure racial and socioeconomic demographics within the geographical vicinity of a clinical site can translate to equitable trial participant representation.
Mismatch repair deficiency and microsatellite instability-high in urothelial carcinoma: A systematic review and meta-analysis.
Authors: Elias Chandran, Giovanni Maria Iannantuono, Dilara Akbulut, Saad Omar Atiq, Sandeep Gurram, Min Yuen Teo, Jonathan Coleman, Ninet Sinaii, Andrea B. Apolo
Journal: Journal of Clinical Oncology (2023)

4570 Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a small subset of urothelial carcinoma (UC) and confer a sensitivity to immunotherapy in multiple solid tumors. Due to the rarity of this patient subset in UC, there is a lack of prospective data on their prevalence or of clinical outcomes with immunotherapy and other treatment modalities. Methods: We performed a systematic review with the objectives of estimating the prevalence of dMMR and MSI-H in urothelial bladder cancer (BC) and upper tract urothelial carcinoma (UTUC) apart from estimating survival and clinical outcomes of treatment. We searched for published prospective and retrospective studies, review articles, case reports, case series, conference proceedings, letters, commentaries, and editorials on dMMR and MSI-H in BC and UTUC published up to 10/26/2022 in PubMed, Cochrane CENTRAL, Embase and Web of Science: Core Collection databases. The study protocol is registered on the PROSPERO database (CRD42022365690). Prevalence data were analyzed using meta-analysis with random-effects models and are reported here. Results: A total of 1,750 studies were screened, of which 125 were included. Thirty-six studies (including 5,113 patients) reported frequencies of dMMR, and 42 studies (including 21,291 patients) reported on MSI-H. Of the total included patients, sex was reported in 11,225, with 72.6% being male and 27.4% female. Age ranged from 17-97 years. Reported primary site was BC in 64.4%, UTUC in 16.3% and not stated in 19.3%. Disease stage reported in 5,341 patients was M0 in 75.0% and M1 in 25.0%. Of the M0 patients, tumor stage data were available in 3,149 patients: Ta-T1 in 33.6% and T2-T4 in 66.4%. The pooled weighted prevalence of dMMR in UC patients was 6% (95% CI 5-8%). The breakdown for BC and UTUC were 2% (95% CI 1-3%) and 9% (95% CI 7-12%), respectively. The three most frequent MMR protein loss patterns in UC, BC and UTUC are shown in the table. Out of 42 studies reporting MSI status, 21 used polymerase chain reaction (PCR) and 21 used next-generation sequencing (NGS). Pooled weighted prevalence of MSI-H in UC was 3% (95% CI 2-3%). In BC, the prevalence was 1% (95% CI 1-1%) and in UTUC, it was 11% (95% CI 8-13%). Conclusions: dMMR and MSI-H were observed more frequently in UTUC than BC. Further analysis on survival and clinical outcomes of dMMR/MSI-H UC with different treatment modalities is ongoing. Additionally, clinical trials in dMMR and/or MSI-H UC are in development to study immunotherapeutic strategies to improve outcomes in both early and advanced stages for this small but important subset of patients. [Table: see text]
Adverse events in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.
Authors: George P. Kim, Michelle Silver, Chad Sanders, Paul Cockrum, Joanna P. MacEwan
Journal: Journal of Clinical Oncology (2023)

e16295 Background: Quality of life is particularly important for patients (pts) with short life expectancy, such as those with metastatic pancreatic ductal adenocarcinoma (mPDAC). While first line (1L) FOLFIRINOX (FFX) is recommended by treatment guidelines for pts with mPDAC and good performance status, the regimen is known to be associated with significant toxicity that impacts quality of life. More than half of pts experience adverse (AEs)—such as nausea and vomiting, diarrhea, fatigue, neuropathy, anemia, thrombocytopenia, and neutropenia—during treatment with FFX. Efforts to reduce AEs have led to the use of modified FFX (mFFX) regimens that utilize lower doses of components of the regimen. Additional evidence on AEs associated with FFX and mFFX in the real world (RW) is needed. We assessed AEs in a RW cohort of mPDAC pts treated with FFX or mFFX in 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between January 2015 and November 2022 who initiated treatment with FFX or mFFX within 90 days of their diagnosis for metastatic disease (1L) were included in the study. Pts were required to have an available body surface area measurement within 7 days of the index date. mFFX was defined as administration of (i) &lt; 150mg/m 2 of irinotecan, or (ii) &lt; 2,720mg/m 2 5-FU total during cycle 1. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Assessment of hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for Adverse Events version 5. Results: Of the 1,326 pts meeting study inclusion criteria and receiving 1L treatment with FFX or mFFX, 1,325 received mFFX and 1 received FFX. The median age at 1L initiation was 65yr (IQR: 58–70), 57% (754 pts) were male, 69% (916 pts) were white, 15% (197 pts) had an ECOG score of 0, 42% (550 pts) had an ECOG score of 1, and 78% (1028 pts) were stage IV at diagnosis. The median number of cycles was 5 (IQR: 3–10) and the median dose intensity per week was 940 mg/m 2 for 5-FU, 179 mg/m 2 for leucovorin, 38 mg/m 2 for oxaliplatin, and 73 mg/m 2 for irinotecan. Notable grade 3/4 AEs were: 16.4% neutropenia, 4.4% thrombocytopenia, 5.7% anemia, 4.7% elevated ALT, 4.9% elevated AST, and 10.6% elevated ALP. Of the ungraded AEs reported in clinician notes, 17.3% of pts experienced diarrhea, 10.9% fatigue, 10.9% nausea and vomiting, and 11.9% neuropathy. Conclusions: In a RW cohort of mPDAC pts treated with 1L FFX or mFFX, nearly all were treated with mFFX. The burden of serious AEs for mPDAC pts during 1L treatment with FFX or mFFX was high, with 30% (403 pts) experiencing at least one grade 3/4 AE.